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  • 1
    Publication Date: 2012-06-23
    Description: Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerji, Shantanu -- Cibulskis, Kristian -- Rangel-Escareno, Claudia -- Brown, Kristin K -- Carter, Scott L -- Frederick, Abbie M -- Lawrence, Michael S -- Sivachenko, Andrey Y -- Sougnez, Carrie -- Zou, Lihua -- Cortes, Maria L -- Fernandez-Lopez, Juan C -- Peng, Shouyong -- Ardlie, Kristin G -- Auclair, Daniel -- Bautista-Pina, Veronica -- Duke, Fujiko -- Francis, Joshua -- Jung, Joonil -- Maffuz-Aziz, Antonio -- Onofrio, Robert C -- Parkin, Melissa -- Pho, Nam H -- Quintanar-Jurado, Valeria -- Ramos, Alex H -- Rebollar-Vega, Rosa -- Rodriguez-Cuevas, Sergio -- Romero-Cordoba, Sandra L -- Schumacher, Steven E -- Stransky, Nicolas -- Thompson, Kristin M -- Uribe-Figueroa, Laura -- Baselga, Jose -- Beroukhim, Rameen -- Polyak, Kornelia -- Sgroi, Dennis C -- Richardson, Andrea L -- Jimenez-Sanchez, Gerardo -- Lander, Eric S -- Gabriel, Stacey B -- Garraway, Levi A -- Golub, Todd R -- Melendez-Zajgla, Jorge -- Toker, Alex -- Getz, Gad -- Hidalgo-Miranda, Alfredo -- Meyerson, Matthew -- CA089393/CA/NCI NIH HHS/ -- CA122099/CA/NCI NIH HHS/ -- R01 CA122099/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 20;486(7403):405-9. doi: 10.1038/nature11154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722202" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Breast Neoplasms/*classification/*genetics/pathology ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor beta Subunit/genetics ; DNA Mutational Analysis ; Exome/genetics ; Female ; Gene Fusion/genetics ; Humans ; Membrane Proteins/genetics ; Mexico ; Mutation/*genetics ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism ; Translocation, Genetic/*genetics ; Vietnam
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-01-07
    Description: Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ojesina, Akinyemi I -- Lichtenstein, Lee -- Freeman, Samuel S -- Pedamallu, Chandra Sekhar -- Imaz-Rosshandler, Ivan -- Pugh, Trevor J -- Cherniack, Andrew D -- Ambrogio, Lauren -- Cibulskis, Kristian -- Bertelsen, Bjorn -- Romero-Cordoba, Sandra -- Trevino, Victor -- Vazquez-Santillan, Karla -- Guadarrama, Alberto Salido -- Wright, Alexi A -- Rosenberg, Mara W -- Duke, Fujiko -- Kaplan, Bethany -- Wang, Rui -- Nickerson, Elizabeth -- Walline, Heather M -- Lawrence, Michael S -- Stewart, Chip -- Carter, Scott L -- McKenna, Aaron -- Rodriguez-Sanchez, Iram P -- Espinosa-Castilla, Magali -- Woie, Kathrine -- Bjorge, Line -- Wik, Elisabeth -- Halle, Mari K -- Hoivik, Erling A -- Krakstad, Camilla -- Gabino, Nayeli Belem -- Gomez-Macias, Gabriela Sofia -- Valdez-Chapa, Lezmes D -- Garza-Rodriguez, Maria Lourdes -- Maytorena, German -- Vazquez, Jorge -- Rodea, Carlos -- Cravioto, Adrian -- Cortes, Maria L -- Greulich, Heidi -- Crum, Christopher P -- Neuberg, Donna S -- Hidalgo-Miranda, Alfredo -- Escareno, Claudia Rangel -- Akslen, Lars A -- Carey, Thomas E -- Vintermyr, Olav K -- Gabriel, Stacey B -- Barrera-Saldana, Hugo A -- Melendez-Zajgla, Jorge -- Getz, Gad -- Salvesen, Helga B -- Meyerson, Matthew -- K07 CA166210/CA/NCI NIH HHS/ -- T32 CA009676/CA/NCI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):371-5. doi: 10.1038/nature12881. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3]. ; 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2]. ; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. ; Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico. ; Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway. ; Tecnologico de Monterrey, Monterrey 64849, Mexico. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. ; Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Facultad de Medicina y Hospital Universitario 'Dr. Jose Eluterio Gonzalez' de la Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico. ; Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway. ; 1] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway. ; Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico [2] Claremont Graduate University, Claremont, California 91711, USA. ; 1] Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway [2] Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, N5020 Bergen, Norway. ; Head and Neck Oncology Program and Department of Otolaryngology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 38109, USA. ; 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2] Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway [3]. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390348" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/genetics/virology ; Carcinoma, Squamous Cell/genetics/virology ; Case-Control Studies ; Cell Cycle Proteins/genetics ; Core Binding Factor beta Subunit/genetics ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; E1A-Associated p300 Protein/genetics ; Exome/genetics ; F-Box Proteins/genetics ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/*genetics ; Genomics ; HLA-B Antigens/genetics ; Humans ; Mitogen-Activated Protein Kinase 1/genetics ; Mutation/*genetics ; NF-E2-Related Factor 2/genetics ; Papillomaviridae/genetics/physiology ; Papillomavirus Infections/genetics ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-ets ; Receptor, ErbB-2/genetics ; Transcription Factors/genetics ; Transcriptome/genetics ; Tumor Suppressor Protein p53/genetics ; Ubiquitin-Protein Ligases/genetics ; Uterine Cervical Neoplasms/*genetics/virology ; Virus Integration/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2011-07-30
    Description: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415217/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stransky, Nicolas -- Egloff, Ann Marie -- Tward, Aaron D -- Kostic, Aleksandar D -- Cibulskis, Kristian -- Sivachenko, Andrey -- Kryukov, Gregory V -- Lawrence, Michael S -- Sougnez, Carrie -- McKenna, Aaron -- Shefler, Erica -- Ramos, Alex H -- Stojanov, Petar -- Carter, Scott L -- Voet, Douglas -- Cortes, Maria L -- Auclair, Daniel -- Berger, Michael F -- Saksena, Gordon -- Guiducci, Candace -- Onofrio, Robert C -- Parkin, Melissa -- Romkes, Marjorie -- Weissfeld, Joel L -- Seethala, Raja R -- Wang, Lin -- Rangel-Escareno, Claudia -- Fernandez-Lopez, Juan Carlos -- Hidalgo-Miranda, Alfredo -- Melendez-Zajgla, Jorge -- Winckler, Wendy -- Ardlie, Kristin -- Gabriel, Stacey B -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- Garraway, Levi A -- Grandis, Jennifer R -- P50 CA097190/CA/NCI NIH HHS/ -- R01 CA077308/CA/NCI NIH HHS/ -- R01 CA098372/CA/NCI NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21798893" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Apoptosis ; Carcinoma/*genetics/metabolism/virology ; Carcinoma, Squamous Cell ; Cell Differentiation ; Exons ; Head and Neck Neoplasms/*genetics/metabolism/virology ; Humans ; *Mutation ; Neoplasms, Squamous Cell/*genetics/metabolism/virology ; Papillomaviridae/isolation & purification ; Papillomavirus Infections/virology ; Point Mutation ; Receptor, Notch1/*genetics/metabolism ; *Sequence Analysis, DNA ; Sequence Deletion ; Signal Transduction ; Smoking ; Tobacco
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2013-06-19
    Description: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919509/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919509/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lawrence, Michael S -- Stojanov, Petar -- Polak, Paz -- Kryukov, Gregory V -- Cibulskis, Kristian -- Sivachenko, Andrey -- Carter, Scott L -- Stewart, Chip -- Mermel, Craig H -- Roberts, Steven A -- Kiezun, Adam -- Hammerman, Peter S -- McKenna, Aaron -- Drier, Yotam -- Zou, Lihua -- Ramos, Alex H -- Pugh, Trevor J -- Stransky, Nicolas -- Helman, Elena -- Kim, Jaegil -- Sougnez, Carrie -- Ambrogio, Lauren -- Nickerson, Elizabeth -- Shefler, Erica -- Cortes, Maria L -- Auclair, Daniel -- Saksena, Gordon -- Voet, Douglas -- Noble, Michael -- DiCara, Daniel -- Lin, Pei -- Lichtenstein, Lee -- Heiman, David I -- Fennell, Timothy -- Imielinski, Marcin -- Hernandez, Bryan -- Hodis, Eran -- Baca, Sylvan -- Dulak, Austin M -- Lohr, Jens -- Landau, Dan-Avi -- Wu, Catherine J -- Melendez-Zajgla, Jorge -- Hidalgo-Miranda, Alfredo -- Koren, Amnon -- McCarroll, Steven A -- Mora, Jaume -- Lee, Ryan S -- Crompton, Brian -- Onofrio, Robert -- Parkin, Melissa -- Winckler, Wendy -- Ardlie, Kristin -- Gabriel, Stacey B -- Roberts, Charles W M -- Biegel, Jaclyn A -- Stegmaier, Kimberly -- Bass, Adam J -- Garraway, Levi A -- Meyerson, Matthew -- Golub, Todd R -- Gordenin, Dmitry A -- Sunyaev, Shamil -- Lander, Eric S -- Getz, Gad -- ES065073/ES/NIEHS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 CA009216/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):214-8. doi: 10.1038/nature12213. Epub 2013 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23770567" target="_blank"〉PubMed〈/a〉
    Keywords: Artifacts ; DNA Replication Timing ; Exome/genetics ; False Positive Reactions ; Gene Expression ; *Genetic Heterogeneity ; Genome, Human/genetics ; Humans ; Lung Neoplasms/genetics ; Mutation/*genetics ; Mutation Rate ; Neoplasms/classification/*genetics/pathology ; Neoplasms, Squamous Cell/genetics ; Oncogenes/*genetics ; Reproducibility of Results ; Sample Size
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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